Abstract

Spinocerebellar ataxia type 3, or Machado–Joseph disease (SCA3/MJD), is caused by an expansion of CAG repeats, which is inversely correlated to age at onset (AO) of symptoms. However, on average, just 55.2% of variation in AO can be explained by expansion length. Additional modulators, such as polymorphic CAG tract in ATXN2 gene, can raise to 63.0% of the variation in AO. A sequence variation (rs3512) in FAN1 gene has previously been shown to be associated with late AO in Huntington’s disease and polyglutaminopathies associated to ataxia. In the present study, genotype frequency of rs3512 was demonstrated in a cohort of SCA3/MJD patients from South Brazil, and these data were correlated to AO. The disease started 2.44 years earlier in subjects with the G/G genotype when compared to those subjects carrying the same CAGexp length at the ATXN3 gene and other genotypes (C/G and C/C) at rs3512. Placing together data on rs3512 genotype with data on CAG tract in ATXN2, AO of patients with G/G genotype was 2.58 years earlier, and a delay of 4.25 years was observed in patients that carry a short ATXN2 allele. Data presented here add further insights on the contribution of other factors in AO of SCA3/MJD beyond the causal mutation. Thus, well-known modifiers can help to unveil new ones and, as a whole, to better elucidate the mechanisms behind disease onset.

中文翻译：

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DNA修复系统基因的变异作为3型脊髓小脑共济失调/马查多–约瑟夫病发病时年龄的附加调节剂

摘要

3型脊髓小脑共济失调或Machado–Joseph病（SCA3 / MJD）是由CAG重复序列的扩增引起的，而CAG重复序列的增加与症状的发作年龄（AO）成反比。但是，平均而言，扩展长度仅可以解释AO变化的55.2％。其他调节剂，例如ATXN2基因中的多态性CAG通道，可以提高AO变异的63.0％。FAN1中的序列变异（rs3512）以前已经证明该基因与亨廷顿舞蹈病中晚期AO和与共济失调有关的多谷氨酰胺病有关。在本研究中，在来自巴西南部的SCA3 / MJD患者队列中证实了rs3512的基因型频率，这些数据与AO相关。与那些在ATXN3基因上具有相同CAGexp长度且在rs3512上具有其他基因型（C / G和C / C）的受试者相比，该疾病在具有G / G基因型的受试者中开始2.44年。将rs3512基因型的数据与ATXN2中的CAG道数据放在一起，G / G基因型患者的AO提前了2. 58年，携带短ATXN2的患者观察到延迟了4.25年。等位基因。本文提供的数据为除因果突变之外的其他因素在SCA3 / MJD的AO中的贡献提供了进一步的见解。因此，众所周知的修饰词可以帮助揭示新的修饰词，并且总体上可以更好地阐明疾病发作的机制。